CN109535238A - A kind of antibacterial peptide Cec4 through structure of modification or its salt and application - Google Patents
A kind of antibacterial peptide Cec4 through structure of modification or its salt and application Download PDFInfo
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- CN109535238A CN109535238A CN201811546382.2A CN201811546382A CN109535238A CN 109535238 A CN109535238 A CN 109535238A CN 201811546382 A CN201811546382 A CN 201811546382A CN 109535238 A CN109535238 A CN 109535238A
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
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- A61P31/04—Antibacterial agents
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Abstract
The present invention provides a kind of antibacterial peptide Cec4 or its pharmaceutically acceptable salt through structure of modification, it is to be obtained one or more amino acid substitutions in antibacterial peptide Cec4 by the way of amino acid substitution, and confirm that it has stronger anti-microbial property, and haemolysis will not be generated, its antibacterial activity liquid is relatively stable under various concentration salt ion condition and trypsinase concentration.The present invention carries out sequence alterations to Cec4, and design derived peptide verifies its anti-microbial property, and analyzes the correlation of reforming mode and antibacterial activity, optimizes for subsequent antibacterial peptide and the application in preparation antibacterials provides effective reference frame.
Description
Technical field
The invention belongs to protein engineering fields, and in particular to a kind of antibacterial peptide Cec4 through structure of modification or its salt and its
Preparing the application in anti-Gram negative bacteria drugs.
Background technique
Antibiotic is the powerful mean treated bacterium infection and cause related disease, but long-term excessively using antibiotic, is caused
Antibody-resistant bacterium mass propagation instead of sensitive strain causes the resistant rate of bacterial antibiotic constantly soaring.Currently, existing many
Referred to as the drug-fast bacteria of superbacteria occurs, and seriously endangers the health of the mankind.Acinetobacter bauamnnii (Acinetobacter
Baumannii), which is a kind of azymic carbohydrate gram-Negative bacillus.In recent years, multidrug resistant and general drug resistance
Acinetobacter bauamnnii is more universal.2017, Carbapenem-resistant class Acinetobacter bauamnnii was classified as 13 classes by WHO and is badly in need of novel antibiosis
First of the emphasis pathogen list of element.Therefore, it is badly in need of developing novel antibacterials to cope with this predicament.Antibacterial peptide
Component part (Antimicrobial peptide, AMP) important as Insect immunity system is that some in organism have
The micromolecule polypeptide of antibacterial activity has the characteristics that small relative molecular mass, thermostabilization, bactericidal range is wide, mechanism of action is unique,
Body induction under by infection or immunostimulation generates antibacterial peptide, is the natural barrier for defending pathogenic microorganism invasion, not only
There is very strong antibacterial ability to bacterium, all there is certain killing activity to fungi, virus, tumour cell etc..Thus, it is not easy to draw
The antibacterial peptide for playing bacterial drug resistance becomes the hot spot of novel antibacterial drug development.
Premenstruum (premenstrua) is the study found that housefly (Musca domestica) cecropin antimicrobial peptides Cec4 is motionless to free Bao Man
Bacillus has preferable antibacterial effect, and (Long Huiling, Yang Juhao, Peng Jian wait housefly cecropin antibacterial peptide Cec4 to Acinetobacter bauamnnii
Research [J] the China's microbiology and Journal of Immunology of bacteriostatic activity, 2017,37 (12): 891-896).Existing research shows
The transformation antibacterial peptide of some processes have to maternal similar or higher activity, and the peptide chain to shorten also reduce synthesis at
This (Boman H G.Antibacterial and antimalarial properties of peptides that are
cecropin-melittin hybrids.Febs Letters,1989,259(1):103-106).By intercepting cecropin
The part peptide chain of CAl9 and in E. coli, antibacterial experiment show that the peptide chain has stronger bacteriostatic activity (poplar
Thin to fawn, Wen Tianan, ten thousand brush lightly thunderclap, wait high efficient expression and activity analysis [J] China of the cecropin A truncated peptide in escherichia coli
Antibiotic magazine, 2010,35 (1), 20-23).Park(Park Y,Lee D G,Jang S H,et al.A Leu-Lys-
rich antimicrobial peptide:activity and mechanism.Biochimica et Biophysica
Acta, 2013,1645 (2): 172-182.) etc. net positive charge and hydrophobicity are improved by Lys replacement and Leu replacement, devise 5
A CA (1-8)-MA (1-12) analog, wherein with Lys replace 4,8,14, No. 15 position amino acid residues and with Leu replace 5,
6, the CA-MA analog of 12,13,16,17, No. 20 position amino acid residues, antibacterial activity and inhibition tumor promotion obtain
Enhancing.Studies have shown that cationic antibacterial peptide charge number is excessive or too small antibacterial peptide and the cell membrane of being all unfavorable for combines, hydrophobicity
Residue, especially C-terminal hydrophobicity should be maintained at a certain range.Hydrophobicity is excessively high, will lead to antibacterial peptide self assemble, reduces and lives
Property, while improving hemolytic, hydrophobicity is too low, can reduce antibacterial peptide to the insertion ability of film, reduce antibacterial activity (Xia Jianghua,
Zhao Wei, Wang Yan, wait synthesis and its antibacterial activity [J] Chinese Journal of Pharmaceuticals of novel cation antibacterial peptide, and 2016,47
(3): 277-281).Thus, influencing the active principal element of antibacterial peptide includes sequence, charge, amphipathic, hydrophobicity, PH, resistance to pancreas
Protease etc..Therefore, structure of modification is carried out to antibacterial Peptide C ec4, is very necessary to promote its antibacterial activity.
Summary of the invention
The object of the present invention is to provide a kind of antibacterial peptide Cec4 through structure of modification, to enhance its bacteriostatic activity, and provides
It is preparing the application in anti-Gram negative bacteria drugs.
In order to achieve the above objectives, the present invention adopts the following technical scheme that:
A kind of antibacterial peptide Cec4 or its pharmaceutically acceptable salt through structure of modification, it is the side using amino acid substitution
Formula obtains one or more amino acid substitutions in antibacterial peptide Cec4.In addition to antibacterial peptide itself, antibacterial peptide of the invention
It can be combined with pharmaceutically acceptable salt, equally there is its drug effect, including (but difference is limited to) and alkali or alkaline earth metal
The salt that (such as sodium, potassium, calcium or magnesium) is formed further includes the salt formed with following inorganic acid: such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, with
And the salt formed with organic acid, and organic acid then refers to acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid and maleic acid.Pharmaceutically
Acceptable salt particular certain cancers.
Preferably, described through tying in the antibacterial peptide Cec4 or its pharmaceutically acceptable salt above-mentioned through structure of modification
The amino acid sequence of the antibacterial peptide Cec4 of structure transformation is as shown in SEQ ID NO:1, SEQ ID NO:2 or SEQ ID NO:3.
Preferably, described through tying in the antibacterial peptide Cec4 above-mentioned through structure of modification or its pharmaceutically acceptable salt
The amino acid sequence of the antibacterial peptide Cec4 of structure transformation is as shown in SEQ ID NO:3.
A kind of antibacterials, active constituent are antibacterial peptide above-mentioned or its pharmaceutically acceptable salt.Foregoing pharmaceutical
Injection, tablet, injection sterile powder, pulvis, granule, capsule, oral liquor and other types of formulations can be made.It is above-mentioned each
Kind dosage form can be prepared using pharmaceutically acceptable carrier according to the conventional method of pharmaceutical field, and injection, mouth can be passed through
Clothes, the method that physically or chemically mediates import muscle, endothelium, subcutaneous, vein, mucosal tissue, or by other material mixings or
Human body is imported after package.
Antibacterial peptide Cec4 above-mentioned through structure of modification or its pharmaceutically acceptable salt are preparing anti-Gram-negative bacteria
Application in drug.
Antibacterial peptide Cec4 above-mentioned through structure of modification or its pharmaceutically acceptable salt are preparing anti-Acinetobacter bauamnnii
Application in drug, Klebsiella Pneumoniae.
Preferably, the antibacterial peptide Cec4 through structure of modification or its pharmaceutically acceptable salt above-mentioned are preparing anti-Bao Man not
Application in lever bacterium drug, the Acinetobacter bauamnnii are standard, multidrug resistant or general drug resistant Acinetobacter bauamnnii,
The Klebsiella Pneumoniae is the Klebsiella Pneumoniae of standard, general drug resistance or multidrug resistant.
The beneficial effects of the present invention are: the present invention provides a kind of antibacterial peptide Cec4 through structure of modification, it is using ammonia
What the mode of base acid replacement obtained one or more amino acid substitutions in antibacterial peptide Cec4, and confirm that it has stronger antibacterial
Performance, and haemolysis will not be generated at higher concentrations, it is anti-under various concentration salt ion condition and trypsinase concentration
Bacterium activity liquid is relatively stable.The present invention carries out sequence alterations to Cec4, and design derived peptide verifies its anti-microbial property, and analyzes transformation
The correlation of mode and antibacterial activity provides effective reference frame for the optimization of subsequent antibacterial peptide, and illustrates to pass through this hair
The bright obtained antibacterial peptide Cec4 through structure of modification is in preparing anti-Gram negative bacteria drugs, especially anti-Bao Man not lever
There is biggish application potential in bacterium and anti-Klebsiella Pneumoniae drug.
Detailed description of the invention
Fig. 1 is that antibacterial peptide Cec4 analyzes the hemolytic of human erythrocyte.
Specific embodiment
The present invention is further introduced with reference to embodiments.
1 material and method
1.1 material
1.1.1 bacterial strain
Standard Acinetobacter bauamnnii (ATCC19606), standard Klebsiella Pneumoniae (ATCC700603) are big by Guizhou medical courses in general
It learns Pathogen Biology laboratory to save, Multi-drug resistant Acinetobacter baumannii (is examined number: 4367661), general drug resistance Bao Man not lever
Bacterium (examine number: 4367992), (examine number: 4363617), general drug resistance Klebsiella Pneumoniae by multidrug resistant Klebsiella Pneumoniae
(inspection number: 4367038) picking up from Guizhou affiliated hospital, medical university, and -80 DEG C of dark places save in 25% glycerol.
1.1.2 antibacterial peptide
It is that basic structure of modification carrys out a series of polypeptides with antibacterial peptide Cec4, amino acid name and sequence are as shown in table 1, go forward side by side
Row chemical synthesis.
The title and sequence (single letter code expression) of 1 Cec4 amino acid substitution peptide of table
In table 1, Cec4 amino acid substitution peptide is respectively Cec4-1 (3 L become R) (corresponding SEQ ID NO:1), Cec4-
2 (2 W become K) (corresponding SEQ ID NO:2), Cec4-3 (39 and 41 K become H), Cec4-4 (37 T become F) are (corresponding
SEQ ID NO:3), Cec4-5 (20,21,22 ATI become AGP), Cec4-6 (30 Q become S), (24 A become Cec4-7
For V), Cec4-8 (3 L become V).
1.1.3 drug and reagent
Sabouraud culture medium, agar powder are purchased from Solarbio company；Peptone, yeast powder are purchased from OXOID company；Sodium chloride purchase
Yu Hengxing Reagent Company；Polymyxin B is purchased from Biosharp company；0.5 Maxwell opacity tube, which is purchased from Beijing Tian An joint science and technology, to be had
Limit company.
1.1.4 instrument
Milli-Q ultrapure water instrument (French Millipore PHarmacia company)；High-pressure sterilizing pot (Japanese ALR)；
PB203-E type precise electronic balance (Shanghai Mei Teletuo benefit instrument company)；(German Eppendorf is public for micro sample adding appliance
Department) digital display stainless steel electric heating incubator (Shanghai is rich to prove to be true after interrogation industry)；Centrifuge (Sigma1-15 high speed tabletop centrifuge, Germany
Sigma company)；Superclean bench (Purifying Equipment Co., Ltd., Suzhou)；Microplate reader (Biotech Epoch 2, the U.S.
BioTeck company).
1.2 method
1.2.1 the design of Cec4 amino acid substitution
Due to cecropin class antibacterial peptide bioactivity by such as net positive charge, hydrophobicity, αhelix stability,
The influence of a variety of physics, chemistry and space structure such as helicity and hinge arrangement.Thus pass through amino acid in the present invention
It replaces to change the quantity of electric charge and hydrophilic and hydrophobic of female Peptide C ec4.
1.2.2 the screening of antimicrobial spectrum and the measurement of MIC value
The Acinetobacter bauamnnii and Klebsiella Pneumoniae for taking logarithmic growth, 1.0 are diluted to MH culture medium ×
106Cfu/mL, the antibacterial peptide Cec4 of bacterium solution and various concentration is added in the every hole of 96 orifice plates and its transformation peptide is experimental group, more Acarasiales
Plain B is positive control, and bacterium solution is negative control, and in 37 DEG C, 120rpm cultivates the U.S. clinical Laboratory Standard of result reference for 24 hours
The criterion of liquid dilution method in the committee (CLSI) visually has no that the drug minimum concentration of bacterial growth is that this is to be measured
The minimum inhibitory concentration (MIC) of bacterium.
1.2.3 it the influence of salt ionic concentration, trypsase antibacterial peptide Cec4 transformation peptide bacteriostatic activity: takes and is grown to logarithmic phase
General drug resistance Acinetobacter bauamnnii, MH culture medium is diluted to 1.0 × 106cfu/mL.Various concentration is added in 96 orifice plates
Cec4 and its transformation peptide mixed with various concentration salt ionic concentration, trypsase after, and and Acinetobacter bauamnnii at 37 DEG C,
120rpm is cultivated for 24 hours, observes its result.
2 results and analysis
The detection of 2.1 Cec4 amino acid substitution peptide antibacterial activity in vitro knows Cec4 to different antibody-resistant bacterium by 2 data of table
For MIC value within the scope of 4~8 μ g/mL, amino acid substitution Peptide C ec4-4 in 2-4mg/L, says the MIC value of different antibody-resistant bacterium
Bright its has stronger anti-microbial property, and different antibody-resistant bacterium are to its sensibility difference.Amino acid substitution Peptide C ec4-3, Cec4-5,
Cec4-8 then illustrates that the amino acid of replacement is that activation plays must amino acid without bacteriostatic activity.
MIC of the 2 Cec4 amino acid substitution peptide of table to all kinds of bacterial strains
Note: Standard Ab is standard Acinetobacter bauamnnii；Pan-resistant Ab is general drug resistance Bao Man not lever
Bacterium；
Multidrug-resistant Ab is Multi-drug resistant Acinetobacter baumannii；Standard Kp is standard pneumonia gram
The primary bacterium of thunder；
Pan-resistant Ab is general drug resistance Klebsiella Pneumoniae；Multidrug-resistant Ab is multidrug resistant
Klebsiella Pneumoniae.
The detection of 2.2 hemolytics
In experiment, as antibacterial peptide Cec4, Cec4-4 concentration is gradually increased to 1mg/mL, hemolysis rate is respectively less than 5%, table
Be now no haemolysis, illustrate antibacterial peptide Cec4, Cec4-4 be to human body in terms of haemolysis it is safe, as a result such as Fig. 1 antibacterial peptide
Cec4 analyzes the hemolytic of human erythrocyte.Criterion is with reference to haemolysis in medical infusion, blood transfusion, the instrument used for injection method of inspection
Experimental judgment standard (2005 medical infusion of Standardization Administration of China .GB/T 14233.2., blood transfusion, syringe
Have Beijing the method for inspection [S]: China Standards Press, 2005:6-7), hemolysis rate is negative reaction less than 5%, and no haemolysis is existing
As；It is positive reaction that hemolysis rate, which is greater than 5%, there is haemolysis.
2.3 ionic intensions to Cec4 transformation peptide antibacterial activity influence: cationic antibacterial peptide by with it is negatively charged
Mantle interaction, to cause cell wall and membrane perforation, eventually leads to bacterial death.It is various present in solution
Ion can cause antibacterial peptide charge to change, to influence its antibacterial activity.Experimental result is shown, with ionic intension
Increase (0~200mM), influence is had no on antibacterial Peptide C ec4 and Cec4-4 bacteriostatic activity, shows that antibacterial peptide Cec4 and Cec4-4 exist
Under the conditions of various concentration salt ion, antibacterial activity is relatively stable (table 3).
Influence of 3 salt ionic concentration of table to Cec4 bacteriostatic activity
Note: "+" representative has bacterial growth；"-" is represented without bacterial growth
Influence of 2.4 trypsinase concentrations to Cec4 and transformation peptide antibacterial activity: oral antibiotic is common administration
Mode, the trypsase in gastric juice has the ability of enzymolysis protein, can destroy the primary structure of antibacterial peptide, so that amino acid forms
It changes, leads to the decline of bacteriostatic activity.High concentrations of trypsin (0.5mg/mL and 1.0mg/mL) and various concentration antibacterial
After Peptide C ec4 and Cec4-4 (0,2,4,8 μ g/mL) are acted on, the results show that in the case where trypsase is 0.5mg/mL effect,
Cec4 and Cec4-4 concentration are that 4 μ g/mL all have antibacterial activity；And when trypsase is increased to 1.0mg/mL, Cec4 concentration is
8 μ g/mL, Cec4-4 concentration are that 4 μ g/mL have antibacterial activity, show that trypsinase concentration is 1~7 times of physiological concentration in solution
When, Cec4-4 still has certain stability (table 4).
Influence of 4 trypsase of table to Cec4 and transformation peptide bacteriostatic activity
Note: "+" representative has bacterial growth；"-" is represented without bacterial growth
In natural antibacterial peptide and not all amino acid sequence is to its antibacterial functions be all it is necessary, purposefully choose peptide chain
Privileged sites or delete unrelated sequences, thus obtain common method that effective small peptide is antibacterial peptide MOLECULE DESIGN (Su Qinghong,
MOLECULE DESIGN progress [J] chemistry and bioengineering of Xu Xiaoqun, Wang Jun Pu's antibacterial peptide, 2012,29 (11): 1-4).It adopts
Housefly cecropin Cec4 is transformed with amino acid substitution method, has studied hydrophilic and hydrophobic and charge change to the shadow of Cec4 antibacterial activity
It rings.It is the key amino acid that Cec4 plays bacteriostatic activity that wherein sequence C ec4-3, Cec4-5, Cec4-8, which replaces amino acid, will be former
After having amino acid substitution, bacteriostatic activity disappears；Though Cec4-1, Cec4-2 can inhibit strain growth, activity is not so good as Cec4, explanation
Cec4 activity cannot be enhanced by increasing N-terminal hydrophily and the quantity of electric charge, it was confirmed that antibacterial activity can be with positive charge in a certain range
Several increases and increase, but can't increase always, when positive changes are more than that certain critical value leads to antibacterial peptide intermolecular electrostatic
The electrostatic attraction of repulsion Qiang Qiyu film hinders the aggregation of antibacterial peptide molecule on film and wears the formation in fenestra road, is eventually exhibited as film
Cracking ability, that is, antibacterial activity decline.Transformation Peptide C ec4-4 enhances 1 times of C-terminal hydrophobicity on the basis of Cec4, and charge number is unchanged, suppression
Bacterium activity is more similar to Cec4, and is greater than Cec4 for Acinetobacter bauamnnii bacteriostatic activity, and increased activity may be with increase C-terminal
Hydrophobicity causes amphiphatic molecule structure composition to change related.In addition, one that the hemolytic of drug is judged as drug safety
Important indicator is shown experimentally that antibacterial peptide Cec4 and Cec4-4 does not generate haemolysis in the dosage range of experiment.With high salt
Under ionic strength, Cec4 and Cec4-4 antibacterial activity is not affected.When trypsase is 0.5mg/mL high physiological concentration
Under effect, Cec4 and Cec4-4 antibacterial activity is relatively stable, but when trypsase rises to 1mg/mL, Cec4-4 is compared with Cec4
Have and preferably resists trypsase ability.
The present invention carries out sequence alterations to Cec4, and design derived peptide verifies its anti-microbial property, and analyzes reforming mode and resist
The active correlation of bacterium, optimizes for subsequent antibacterial peptide and the application in preparation antibacterials provides effective reference frame,
And illustrate through the invention the obtained antibacterial peptide Cec4 through structure of modification in preparing anti-Gram negative bacteria drugs, it is outstanding
It is that have biggish application potential in anti-Acinetobacter bauamnnii drug and anti-Klebsiella Pneumoniae drug.
Sequence table
<110>Guizhou medical university
<120>a kind of antibacterial peptide Cec4 and its application through structure of modification
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 41
<212> PRT
<213>artificial sequence (unknown)
<400> 1
Gly Trp Arg Lys Lys Ile Gly Lys Lys Ile Glu Arg Val Gly Gln Asn
1 5 10 15
Thr Arg Asp Ala Thr Ile Gln Ala Ile Gly Val Ala Gln Gln Ala Ala
20 25 30
Asn Val Ala Ala Thr Leu Lys Gly Lys
35 40
<210> 2
<211> 41
<212> PRT
<213>artificial sequence (unknown)
<400> 2
Gly Lys Leu Lys Lys Ile Gly Lys Lys Ile Glu Arg Val Gly Gln Asn
1 5 10 15
Thr Arg Asp Ala Thr Ile Gln Ala Ile Gly Val Ala Gln Gln Ala Ala
20 25 30
Asn Val Ala Ala Thr Leu Lys Gly Lys
35 40
<210> 3
<211> 41
<212> PRT
<213>artificial sequence (unknown)
<400> 3
Gly Trp Leu Lys Lys Ile Gly Lys Lys Ile Glu Arg Val Gly Gln Asn
1 5 10 15
Thr Arg Asp Ala Thr Ile Gln Ala Ile Gly Val Ala Gln Gln Ala Ala
20 25 30
Asn Val Ala Ala Phe Leu Lys Gly Lys
35 40
Claims (7)
1. a kind of antibacterial peptide Cec4 or its pharmaceutically acceptable salt through structure of modification, which is characterized in that it is using amino
What the mode of acid replacement obtained one or more amino acid substitutions in antibacterial peptide Cec4.
2. the antibacterial peptide Cec4 or its pharmaceutically acceptable salt, feature according to claim 1 through structure of modification exists
In amino acid sequence such as SEQ ID NO:1, SEQ ID NO:2 or the SEQ ID of the antibacterial peptide Cec4 through structure of modification
Shown in NO:3.
3. the antibacterial peptide Cec4 or its pharmaceutically acceptable salt, feature according to claim 2 through structure of modification exists
In the amino acid sequence of the antibacterial peptide Cec4 through structure of modification is as shown in SEQ ID NO:3.
4. a kind of antibacterials, which is characterized in that its active constituent be the described in any item antibacterial peptides of claims 1 to 3 or its
Pharmaceutically acceptable salt.
5. the described in any item antibacterial peptide Cec4 through structure of modification of claims 1 to 3 or its pharmaceutically acceptable salt are being made
Application in standby anti-Gram negative bacteria drugs.
6. the described in any item antibacterial peptide Cec4 through structure of modification of claims 1 to 3 or its pharmaceutically acceptable salt are being made
Application in standby anti-Acinetobacter bauamnnii, Klebsiella Pneumoniae drug.
7. the antibacterial peptide Cec4 according to claim 6 through structure of modification or its pharmaceutically acceptable salt are anti-in preparation
Application in Acinetobacter bauamnnii drug, which is characterized in that the Acinetobacter bauamnnii is standard, multidrug resistant or general drug resistance
Acinetobacter bauamnnii, the Klebsiella Pneumoniae be standard, general drug resistance or multidrug resistant Klebsiella Pneumoniae.
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|---|---|---|---|
| CN201811546382.2A CN109535238B (en) | 2018-12-18 | 2018-12-18 | Structurally-modified antibacterial peptide Cec4 or salt thereof and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811546382.2A CN109535238B (en) | 2018-12-18 | 2018-12-18 | Structurally-modified antibacterial peptide Cec4 or salt thereof and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1365981A (en) * | 2001-01-19 | 2002-08-28 | 山东大学 | Antibacterial peptide gene of fly and its cloning process |
| CN106366172A (en) * | 2016-10-17 | 2017-02-01 | 黑龙江八农垦大学 | Bigeminal peptide Cec Md2ys, preparation method and application |
-
2018
- 2018-12-18 CN CN201811546382.2A patent/CN109535238B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1365981A (en) * | 2001-01-19 | 2002-08-28 | 山东大学 | Antibacterial peptide gene of fly and its cloning process |
| CN106366172A (en) * | 2016-10-17 | 2017-02-01 | 黑龙江八农垦大学 | Bigeminal peptide Cec Md2ys, preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| PRAVEEN RISHI等: "Efficacy of designer K11 antimicrobial peptide (a hybrid of melittin, cecropin A1 and magainin 2) against Acinetobacter baumannii-infected wounds", 《PATHOGENS AND DISEASE》 * |
| 吴兆颖等: "《第十三届全国免疫学学术大会摘要汇编》", 7 November 2018 * |
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